1 Roles & Responsibilities of the Research Team Developed by Center for Cancer Research, National Cancer Institute, NIH Endorsed by the CTN SIG Leadership Group
2 Introduction All staff involved in clinical research must adhere to the regulations and understand the guidelines that govern clinical research. This module will provide an overview of the roles and responsibilities of the research team and other staff including: Investigator, Clinical Trial Nurse (CTN), Clinical Data Manager, Staff Nurse, and Pharmacist. At the conclusion of this module, you will be able to: Describe the role and responsibilities of the Investigator as described by OHRP, FDA, and ICH. Describe the role and responsibilities of the CTN. Describe the role and responsibilities of the Clinical Data Manager. Describe the role and responsibilities of the Staff Nurse. Describe the role and responsibilities of the Pharmacist.
3 OHRP s Use of Investigator OHRP interprets an investigator to be any individual who is involved in conducting human subjects research studies. Such involvement would include: obtaining information about living individuals by intervening or interacting with them for research purposes; obtaining identifiable private information about living individuals for research purposes; obtaining the voluntary informed consent of individuals to be subjects in research; and studying, interpreting, or analyzing identifiable private information or data for research purposes.
4 OHRP s Use of Investigator (continued) Investigators can include physicians, scientists, nurses, administrative staff, teachers, and students, among others. With multiple investigators, one investigator is designated the principal investigator with overall responsibilities for the study. The next several pages will review OHRP s current thinking on the role of the investigator. To learn more, review OHRP s Investigator Responsibility Frequently Asked Questions
5 Investigator Responsibilities Design and implement ethical research, consistent with three ethical principles delineated in the Belmont report Comply with all applicable federal regulations impacting the protection of human subjects Ensure that all research involving human subjects is submitted to and approved by the appropriate institutional review board
6 Investigator Responsibilities Comply with all applicable IRB policies, procedures, decisions, conditions, and requirements Implement research as approved and obtain prior IRB approval for changes Obtain informed consent and assent in accord with federal regulations and as approved by the IRB Document informed consent and assent in accord with federal regulations and as approved by the IRB
7 Investigator Responsibilities Report progress of approved research to the IRB, as often and in the manner prescribed by the IRB Report to the IRB any injuries, adverse events, or other unanticipated problems involving risks to subjects or others Retain signed consent documents and IRB research records for at least 3 years past completion of the research activity
8 FDA and the Role of the Investigator FDA defines the responsibilities of the Investigator when conducting FDA regulated research. All Investigators should refer to 21 CFR Parts 11, 50, 54, 56, 312, and 812 for a more comprehensive listing of FDA's requirements. The Investigator is the one who has the overall responsibility for the conduct of the clinical trial and is often referred to as the PI in the protocol document as Other Investigators are referred to as Subinvestigators by the FDA or in the NIH community an Associate Investigator (AIs).
9 Role of the Investigator: Drugs or Biologics An investigator s responsibilities in conducting clinical investigations of drugs or biologics are provided in 21 CFR Part 312 Many of these responsibilities are included in the required investigator s signed statement, Form FDA-1572 Page 2, Section 9 lists the commitments of the Investigator which appear on the next several slides
10 Investigator Commitments Conduct study in accordance with the relevant, current protocol and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, right, or welfare of subjects Personally conduct or supervise the described investigation
11 Investigator Commitments Inform any patients, or any persons used as controls, that the drugs are being used for investigational purposed and ensure requirement relating to obtaining informed consent in 21 CFR Part 50 and IRB review and approval in 21 CFT Part 56 are met Agree to report to sponsor adverse experiences that occur in the course of the investigation in accordance with 21 CFR
12 Investigator Commitments Read and understand the information in the investigator's brochure, including the potential risks and side effects of the drug Agree to ensure all associates, colleagues, and employees assisting in the conduct of the study are informed about their obligations in meeting the previous commitments
13 Investigator Commitments Maintain adequate and accurate records in accordance with 21 CFR and to make those records available for inspection in accordance with CFR Ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation Promptly report to the IRB all changes in research activity and all unanticipated problems involving risks to human subjects or others. Make no changes in the research w/o IRB approval expect where necessary to eliminate apparent immediate hazard to human subjects.
14 Investigator Commitments Comply with all other requirements regarding the obligation of clinical investigators and all other pertinent requirements in 21 CFR Part 312
15 Form 1572 Form 1572 is updated as needed There is one Form 1572 per study Exception: CTEP-sponsored trials have 1 form per investigator and must be updated at least annually. See their website for more information about Investigator registration for CTEPsponsored trials. All copies of the Form 1572 are to be maintained in the regulatory binder. To learn more, review FDA s 2010 Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions Statement of Investigator (Form FDA 1572)
16 Role of the Investigator: Devices An investigator s responsibilities in conducting clinical investigations of a medical device are provided in 21 CFR Part 812, including the requirement that there be a signed agreement between the investigator and sponsor (see 21 CFR (c)(4) and ). Device regulations do not require the use of a specific form for an investigator s statement.
17 FDA Guidance The following FDA guidance document provides an overview of the responsibilities of a person who conducts a clinical investigation of a drug, biological product, or medical device (an investigator as defined in 21 CFR 312.3(b) and 21 CFR 812.3(i)). Investigator Responsibilities Protecting the Rights, Safety, and Welfare of Study Subjects This guidance provides information for the Investigator on: Supervisory activities associated with the conduct of a clinical trial including: What is appropriate delegation of study-related tasks What is adequate training What is adequate supervision of the conduct of ongoing clinical trial What are Investigator's responsibilities for oversight of other parties involved in the conduct of a clinical trial? Protecting the rights, safety, and welfare of study subjects Reasonable medical care Reasonable access to medical care Protocol violations that present unreasonable risk ALL research team members should review this document.
18 International Conference on Harmonisation (ICH) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use is an agreement between the European Union, Japan and the United States to harmonize different regional requirements for registration of pharmaceutical drug products Unique joint effort by regulators and associated pharmaceutical industry trade associations ICH guidelines have been adopted as law in several countries, but are only used as guidance for the U.S. Food and Drug Administration
19 International Conference on Harmonisation (ICH) Guidances 4 major categories of standards are: Quality guidelines chemical and pharmaceutical Quality Assurance Safety guidelines in vitro and in vivo pre-clinical studies Efficacy guidelines E1-E2F: Clinical safety E6: Good Clinical Practice (GCP) Guidelines Multidisciplinary guidelines cross-cutting topics that do not fit into one of the above categories
20 E6: Good Clinical Practice (GCP) Guidelines This document: Describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs Covers aspects of monitoring, reporting and archiving in clinical trials Describes the essential documents that are to be maintained by the site and the sponsor The next several pages provide a summary of the Investigator s responsibilities as described in E6 Section 4.
21 E6: Investigator Qualifications & Agreements The Investigator should: Be qualified (documented) by education, training & experience to assume responsibility for proper trial conduct Be familiar with the appropriate use of the investigational product, IB, and other information provided by sponsor Be aware of, & should comply with, GCP and the applicable regulatory requirements Permit monitoring, auditing and inspection Delegate duties to appropriately qualified persons
22 E6: Adequate Resources The Investigator should: Demonstrate adequate potential for recruitment Have sufficient time for trial conduct and completion Have adequate staff and facilities to conduct the trial Ensure training to staff
23 E6: Medical Care of Trial Subjects The Investigator should: Ensure that qualified physician investigators/sub investigators for the trial, should be responsible for all trial related medical decisions Adequate medical care during and after trail participation Make reasonable efforts ascertaining for premature withdrawal from trial Inform subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
24 E6: Communication with IRB The Investigator should: Seek written & dated approval for trial protocol, informed consent document, recruitment procedures, etc. prior to trial initiation Provide latest copies of Investigator Brochure (IB) to IRB Provide all relevant documents for review during trial
25 E6: Compliance with Protocol The Investigator should: Conduct trial in accordance with the protocol version agreed & documented by the sponsor, IRB and regulatory authority Ensure that no changes are allowed in the protocol except in case of immediate hazard to the patient
26 E6: Investigational Product The Investigator: Is responsible for investigational product accountability at the site May be assigned to pharmacist/individual Ensure that investigational product is stored as specified by sponsor or regulatory authority Ensure that the investigational product is used only in accordance with the protocol
27 E6: Randomization Procedures and Unblinding The Investigator: Should follow the trial s randomization procedure Report any premature unblinding to be explained to sponsor
28 E6: Informed Consent.. The Investigator should: Comply with regulatory requirement, GCP and ethical principles Document communication of revised consent document to IRB and patient Not influence or coerce subject to participate Ensure that the subject or their legal representative is fully informed in their own language Review Subject's responsibilities as part of the informed consent process
29 E6: Informed Consent The Investigator should: Ensure that the informed consent document does not contain technical language Allow ample time for the consent process and opportunity for exchange of information or subject questions Provide an impartial witness for illiterate patients Provide the Subject with a copy of the signed and dated Informed Consent Document
30 E6: Records and Reports The Investigator: Should ensure accuracy, completeness, legibility and timeliness of data to sponsor in CRF Ensure corrections on a CRF be signed and dated Should maintain trial related documents Ensure all financial agreements are in place prior to subject enrollment Provide access to records by monitor, regulatory agency or auditors Submit progress reports to IRB
31 E6: Safety Reporting The Investigator should: Report all serious adverse events, including deaths, to sponsor and IRB/regulatory agency as per SOPs See Adverse Event Module for more information on adverse event reporting
32 E6: Premature Termination of Trial The Investigator should: Inform subjects Assure therapy and follow up Inform sponsor, IRB, and other regulatory authorities as per SOPs
33 E6: Final Report Upon completion of the study, the Investigator should provide the IRB and other regulatory authorities with a summary of the trial s outcome
34 Sub-Investigator The definition of "sub-investigator" in FDA's official guidance, the "ICH E-6 Good Clinical Practice: Consolidated Guidance," states: "Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and//or to make important trial-related decisions (e.g., associates, residents, research fellows)." It's important to recognize that any study staff who "make direct and significant contribution to the data" are considered "sub-investigators" which means they would also need to be listed in block #6 of the Form FDA This may include the CTN.
35 Nurses and Clinical Research Nurses involved in clinical research continue to serve as advocates for their patients. However, the now take on 2 additional advocate roles: Subject advocate Protocol advocate The trick is learning how to balance all 3 advocacy roles. Nurses may play a role in study coordination or care for patients on a clinical trial or do both.
36 Clinical Trials Nurse As defined in the ONS CTN competencies, the CTN demonstrates critical thinking and implementation of the nursing process, thus providing leadership in the conduct of clinical trials, improving outcomes for patients, and enhancing study integrity. This is accomplished through competent practice in the following functional areas : Protocol compliance Clinical Trials Related Communication Informed Consent Process Management of Clinical Trial Patients Documentation Patient Recruitment Ethical Issues Professional Development The next several pages will highlight these competencies.
37 Protocol Compliance Adheres to current regulations, guidance, and policies that affect research at the institutional, state, federal, and international levels. Complies with the processes and procedures required by different types of sponsors (e.g., private industry, National Cancer Institute Cancer Therapy Evaluation Program, investigator-initiated). Ensures security of research data and personal health information. Participates in discussions regarding feasibility of protocol implementation based on knowledge of institutional capabilities and limitations, therapy, or population of interest. Collaborates with the research team to implement procedures for maintaining patient study participation from enrollment through completion.
38 Protocol Compliance Participates in providing timely, informative, and accurate communication to the IRB as required. Facilitates and participates in the preparation for and implementation of scheduled and unscheduled meetings with external and internal monitors and auditors (e.g., sponsors, FDA, IRB, QA). Ensures validity of research results by ensuring timely, accurate, and complete data documentation, reporting deviations, violations, and serious adverse events. Collaborates with principal investigator, pharmacy, and other appropriate personnel to ensure proper use of and accountability for experimental devices or drugs as indicated.
39 Clinical Trials Related Communication Ensures ongoing formal and informal communication regarding clinical trials with team members. Provides general clinical research as well as trialspecific information to research, clinical, and other organizational staff. Develops relationships with referring physicians, clinical staff, and ancillary departments to facilitate compliance with and accrual to clinical trials. Participates in study initiation meetings. Provides education related to clinical trials to patients and their significant others. Advocates for the safety and care of clinical trial patients as well as for the promotion and integrity of the clinical trial
40 Informed Consent Process Ensures the initial and ongoing consent process is performed and documented in compliance with FDA, International Conference on Harmonization Good Clinical Practice (GCP), institutional, sponsor, IRB, and other applicable regulations, guidances, and policies. Participates in the education of clinical trial patients about their clinical trial and significant new information that is forthcoming during or after the conduct of the trial. Assesses for barriers to effective informed consent discussions and implements plans to overcome them.
41 Management of Clinical Trial Patients Collaborates with the investigator to ascertain study patient eligibility for a clinical trial, including documentation of criteria specified in the protocol. Ensures adherence to the protocol schedule of events and other requirements. Ensures scheduling of all procedures required to assess for adverse events and disease response to the study intervention. Ensures the successful completion of correlative components of the clinical trial (e.g., pharmacokinetic, pharmacoeconomic, and quality-of-life studies). Assesses patients for trial-related and non trial-related symptoms and ensures evidence-based symptom management while maintaining trial compliance.
42 Management of Clinical Trial Patients In collaboration with the investigator, assesses patients for adverse events and then documents and reports these findings per the protocol, sponsor, IRB, FDA, and OBA regulations. Utilizes adverse event assessment data and clinical judgment to determine if a dose-limiting toxicity has occurred or if any treatment schedule or drug dose modifications are necessary and communicates findings to the study team and sponsors. Evaluates disease response results and physical assessment data in conjunction with the principal investigator to determine response per the protocol. Supports and evaluates patient adherence to the protocol by utilizing various methods to assist with documentation, patient education, and study agent return. Identifies vulnerable patients who require increased nursing assessment and management in addition to the clinical trial requirements.
43 Documentation Complies with regulations, institutional policies, and sponsor requirements governing source data and documentation. Documents assessment, management, and evaluation in source documents for patients on clinical trials as appropriate to the protocol and role. Educates research and clinical team members regarding appropriate and accurate source documentation for participants in clinical trials. Ensures that relevant data from the source document are abstracted and recorded in the clinical trial case report forms and that every data point can be verified within the source document.
44 Documentation Follows appropriate guidelines in making corrections to data entry in clinical records and case report forms as recommended by good clinical practices, standards, or institutional procedures. Ensures that all regulatory documents are processed and maintained per institution, IRB, and GCP. Demonstrates proficiency in the use of clinical and research-related computer programs.
45 Patient Recruitment Assists in implementation of recruitment plans to identify and assess individuals who might be eligible for clinical trials, taking into consideration the study entry criteria, required procedures, and other potential factors. Identifies and develops processes to overcome barriers to recruitment related to patient demographic factors, underserved populations, and healthcare system influences. Identifies institutional or community-based resources or groups that can assist in achieving recruitment goals
46 Ethics Advocates for ethical care of clinical trial patients and the conduct of clinical trials in accordance with standards of nursing practice. Promotes ongoing compliance with key ethical concepts by the research team, including informed consent, documentation, respect for persons, beneficence, and justice. Ensures that members of vulnerable populations enrolled in clinical trials are identified and that their rights are addressed. Identifies and follows institutional procedures to report any falsification of data or scientific misconduct.
47 Financial Implications Describes the key components included in study budgets and institutional resources for budget details. Confers with the principal investigator or finance personnel when protocol revisions will affect the costs of protocol management. Identifies routine care versus research-related costs, the financial impact on patients, and any need for financial counseling. Ensures and tracks submission of specified items (e.g., completed case report forms, specimens) to facilitate timely recovery of protocol-related activity costs. Ensures that stipends to patients for protocol-related activities are disclosed to the IRB during approval of the consent form.
48 Professional Development Participates in educational opportunities to increase knowledge about clinical trials, regulations and guidance, and the role of the CTN. Seeks resources on an ongoing basis that provide oncology treatment and nursing practice updates, such as through professional mentoring and meetings, journals, and Web sites.
49 Clinical Data Manager (CDM) Individual responsible for some or all activities related to Clinical Data Management: Data acquisition/collection Data abstraction/extraction Data processing/coding Data analysis Data transmission Data storage Data privacy Data QA Clinical data management is a multi-disciplinary activity that includes: Investigators CTNs Clinical data managers Support personnel Biostatisticians Database programmers
50 CDM Responsibilities Collects source documents needed for data abstraction Abstracts research data from patient s medical record/source documents to the case report form (paper or electronic) Enters data into database(s)
51 CDM Responsibilities Conducts self-audits to ensure data quality Manages protocol related data (i.e.: understanding what forms are still outstanding and what documentation is missing) Understands how CRFs are developed
52 CDM Responsibilities Understands the various databases used and how to resolve problems associated with the different systems Provides periodic reports from database Helps to prepare for audits/monitoring visits
53 Study Subject s Responsibilities The study subject has responsibilities as an integral member of clinical research. Their role needs to be reinforced as part of the informed consent process. Roles include: Adhering to protocol specific schedule of events Timely notification to the research staff including: Adverse events Changes in concomitant medications Inability to comply with protocol criteria (e.g.: exclusionary meds, keeping appointments, patient diaries, etc.) Change in status (e.g.: new phone #, adverse event, etc.) in a timely manner
54 Staff Nurse Provides direct patient care including treatment and patient education Adheres to protocol Documents all patient encounters in the medical record Collects specimen as per protocol Informs PI/CTN of patient or protocol related issues/concerns
55 Pharmacist Though the PI is ultimately accountable for drug accountability, this is often delegated to a pharmacist: Prepares drugs as per protocol Stores investigational products as per protocol For multiple studies using same IND agent, needs to provide separate/distinct storage in pharmacy Maintains accurate drug accountability records Receipts of drug shipment/invoices Drug accountability record form (DARF)
56 Example of a DARF
57 Helpful Hints: Know Your Protocols Eligibility criteria Drug preparation & administration Schema, requirements, follow-up PKs, research tests, restaging, drug return Dose limiting toxicity and/or dose modifications Reporting requirements Results (responses, toxicities)
58 Helpful Hints: Know the Disease Etiology Epidemiology Signs and Symptoms Screening and Diagnosis Pathology Grading Disease Staging Treatment Options What is standard therapy? Disease Trajectory Clinical Trials elsewhere for the same disease
59 Regardless of Your Role: Be Your Own Best Advocate Protect your time & get organized Learn as much as you can about: clinical trials oncology your particular drug(s) your database/software programs Know how/where to get training & do it Join a professional organization & get involved Teach something new & you will learn Teach someone new & you will grow
60 Module Evaluation The CTN SIG would greatly appreciate your feedback on this learning module. Please complete the evaluation form and fax to Elizabeth Ness at